Seminars in Neurology最新文献

Circadian rhythms (CRs) are entrainable endogenous rhythms that respond to external stimuli and regulate physiological functions. The suprachiasmatic nucleus (SCN) in the hypothalamus is the mammalian master clock that synchronizes all other tissue-specific peripheral clocks, primarily through gamma-aminobutyric acid (GABA) and vasoactive intestinal polypeptide (VIP). The SCN follows Earth's 24-hour cycle by light entrainment through the retinohypothalamic tract. At the cellular level, the core clock genes CLOCK, BMAL1, PER1-PER3, CRY1, and CRY2 regulate CRs in a negative feedback loop. The circadian disruption of the sleep-wake cycle manifests in at least six distinct clinical conditions. These are the circadian rhythm sleep-wake disorders (CRSWDs). Their diagnosis is made by history, sleep diaries, and actigraphy. Treatment involves a combination of timed light exposure, melatonin/melatonin agonists, and behavioral interventions. In addition, CR disturbances and subsequent misalignment can increase the risk of a variety of illnesses. These include infertility and menstrual irregularities as well as diabetes, obesity, fatty liver disease, and other metabolic syndromes. In addition, a disruption in the gut microbiome creates a proinflammatory environment. CR disturbances increase the risk for mood disorders, hence the utility of light-based therapies in depression. People with neurodegenerative disorders demonstrate significant disturbances in their CRs, and in their sleep-wake cycles. Circadian realignment therapies can also help decrease the symptomatic burden of these disorders. Certain epilepsy syndromes, such as juvenile myoclonic epilepsy (JME), have a circadian pattern of seizures. Circadian disturbances in epilepsy can be both the consequence and cause for breakthrough seizures. The immune system has its own CR. Disturbances in these due to shift work, for instance, can increase the risk of infections. CR disturbances can also increase the risk of cancer by impacting DNA repair, apoptosis, immune surveillance, and cell cycle regulation. Moreover, the timing of chemotherapeutic agents has been shown to increase their therapeutic impact in certain cancers.

Sleep disturbances and cognitive decline are intricately connected, and both are prevalent in aging populations and individuals with neurodegenerative disorders such as Alzheimer's disease (AD) and other dementias. Sleep is vital for cognitive functions including memory consolidation, executive function, and attention. Disruption in these processes is associated with cognitive decline, although causal evidence is mixed. This review delves into the bidirectional relationship between alterations in sleep and cognitive impairment, exploring key mechanisms such as amyloid-β accumulation, tau pathology, synaptic homeostasis, neurotransmitter dysregulation, oxidative stress, and vascular contributions. Evidence from both experimental research and population-based studies underscores the necessity of early interventions targeting sleep to mitigate risks of neurodegenerative diseases. A deeper understanding of the interplay between sleep and cognitive health may pave the way for innovative strategies to prevent or reduce cognitive decline through improved sleep management.

Excessive daytime sleepiness (EDS) is common. However, clinical features of excessive sleepiness can have broad and variable presentations. In addition, there can be an increased likelihood of medical or psychiatric comorbidity. Examination of the networks that regulate sleep-wake and circadian control reveals a complex and intricately designed integration system. Dysregulation in the coordination, effectiveness, or efficiency of these systems can contribute to developing EDS, and inform on the endotypes observed and pharmacologic considerations for treatment. The discovery and characterization of the diurnal expression and function of orexin (hypocretin) have led to a transformed understanding of sleep-wake control and EDS, as well as its role beyond sleep. As a result, a novel drug class, orexin agonists, is anticipated to emerge for clinical use in the near future. An understanding of orexin physiology and its transdisciplinary impact is necessary to best prepare for patient selection, use, and anticipated benefit and monitoring of both expected benefits and any other health change. This study provides a review of the range of clinical features and impact of EDS, the relationship between sleep-wake, circadian and other health networks, and an examination of orexin physiology with anticipatory guidance on the potential transdisciplinary role and impact of orexin agonists.

α-synucleinopathies are a complex group of progressive neurodegenerative disorders with an increasingly recognized long prodromal period, during which sleep dysfunction is a hallmark. Sleep disorders during the prodromal synucleinopathy period, primarily isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and daytime hypersomnolence correlate best with the recently proposed "body-first" Lewy body disease progression. iRBD is the most widely recognized form of prodromal α-synucleinopathy, and patients with iRBD show abnormal α-synuclein in tissues and biofluids even in the absence of cognitive or motor symptoms. More importantly, individuals with iRBD have an elevated risk for near-term development of a clinically diagnosable symptomatic synucleinopathy. Other sleep disorders such as hypersomnia and circadian rhythm dysfunction also occur across the synucleinopathy spectrum, although their prognostic significance is less well understood than iRBD. Finally, isolated REM sleep without atonia may represent an even earlier stage of prodromal synucleinopathy, but further studies are needed.

After experiencing a traumatic brain injury (TBI), the majority of patients will develop sleep-wake disorders (SWD). These can include insomnia, posttraumatic pleiosomnia (increased sleep need), excessive daytime sleepiness (EDS), obstructive and/or central sleep apnea, circadian SWD, and a variety of parasomnias. Untreated SWD may impede the recovery process and can negatively impact mood, metabolic health, cognitive function, and immune function among other processes. Importantly, these patients tend to misperceive their posttraumatic sleep problems. Consequently, interviews performed in standard clinical practice may not sufficiently capture SWD patients, potentially compromising safety and productivity. In this up-to-date review, we outline the state of current TBI-related SWD, highlighting proposed mechanisms, treatment modalities, and areas for further clinical investigation. We discuss data supporting the role of slow wave sleep in the enhancement of neural recovery and strengthening of healthy neural circuits. We also examine the utility of enhanced cohort recruitment and SWD biomarker discovery via the use of social media, smart devices, and data-sharing networks, and call for increased research in the intersection of TBI and SWD.

The immune system and sleep are inextricably linked in both health and pathological conditions. Tightly regulated neuroimmune processes are critical for the physiological maintenance of healthy sleep. Reciprocally, sleep disturbances can detrimentally affect immune homeostasis and predispose to increased risk of autoimmune conditions, which themselves are bidirectionally associated with a higher risk of sleep disturbances. Autoimmune diseases of the central nervous system (CNS), particularly conditions that affect neuroanatomical regions involved in sleep homeostasis and nocturnal respiration, are associated with an increased risk sleep disorders that may impact diagnosis, clinical course, and management. This review summarizes the bidirectional relationship between sleep and immunity and highlights several exemplar autoimmune conditions of the CNS that include sleep disorders as a consequence or diagnostic feature of the disorder.

Sleep is a vital function, taking about one-third of a human lifetime, and is essential for achieving and maintaining brain health. From homeostatic neurophysiology to emotional and procedural memory processing to clearance of brain waste, sleep and circadian alignment remain paramount. Yet modern lifestyles and clinical practice often dismiss sleep, resulting in profound long-term repercussions. This chapter examines the roles of sleep and circadian rhythms in memory consolidation, synaptic plasticity, and clearance of metabolic waste, highlighting recent advances in neuroscience research. We explore how insufficient and disordered sleep-a public health concern-can impair cognition, escalate neurodegenerative risks, and compromise neurovascular integrity, thereby impacting brain health. These findings underscore the need for comprehensive screening for disturbed sleep and targeted interventions in clinical practice. Emerging interventions and AI-driven technologies may allow early detection and personalized and individualized treatments and improve outcomes. Overall, this chapter reaffirms that healthy sleep is indispensable at any level of neurological disease prevention-on par with the role of diet and exercise in cardiovascular health-and represents the foundation of brain health.

Restless legs syndrome (RLS) is a complex sensorimotor disorder characterized by disturbances in key neurochemical pathways, including dopaminergic, glutamatergic, and adenosinergic systems. This review provides an overview of the current knowledge on RLS, including its clinical features and diagnosis, pathophysiology, and treatment (non-pharmacological and pharmacological). We examine the association between RLS and neurological disorders, genetic predispositions, and brain iron deficiency. Emerging therapies targeting glutamate and adenosine receptors, alongside established dopamine agonists and α2δ ligands, offer promising avenues for treatment.